beta-substituted-delta alpha,beta-gamma-butyrolactones and methods of preparing them



Patented Aug. 22, 1944 UNITED. STATES PATENT OFFICE fi-SUBSTITUTED-A -B-y-BUTYROLACTONES AND METHODS OF PREPARING THEM Robert C. Elder-field, Hastings on Hudson, N. Y., and Martin Rubin, Baltimore, Md., assignors to Eli Lilly and Company, Indianapolis, Ind., a corporation of Indiana No Drawing. Application March 21, 1941, Serial No. 384,587

7 Claims. (Cl. 260-344) Grignards reagent. A Grignards reagent is anyone of a group of organic magnesium compounds of the general type Ra-Mg-Y in which R3 is an organic radical and Y is a halogen selected from the class consisting of chlorine, bromine, and iodine. The aromatic group may contain one or more substituents such as hydroxyl, alkyl, alkenyl and alkoxy. Sometimes it is necessary to protect the substituent group in order to form the required Grignards reagent. The compound of the protected group forms with magnesium the required Grignards reagent.

The compositions of this invention are prepared by reacting a compound represented by the formula:

2) R-M -x in which R. has the same meaning as before and X is a halogen of the class consisting of chlorine,

bromine, and iodine, to the action of an alkoxyacetonitrile. This action may be represented by l the following equation:

in which R1 is an alkyl radical, preferably the ester of a haloacetic acid selected from the class which consists of chloroacetic acid, bromoacetic l acid, and iodoacetic acid (ZCHz.COOR-z in which .R2 represents an alkyl radical, preferably the methyl or ethyl radical, and Z represents chlorine, bromine, or iodine) in the presence of zinc.

in an inert solvent, such as benzene or toluene. Preferably, this mixture is refluxed and the reaction product is treated with an aqueous solution of a mineral acid, such as hydrochloric acid, which is cooled to'approximately 0 C., and separated from inorganic constituents to form an ester of fl-R-p-hydroxy-p-alkoxymethyl propionic acid. The action which takes place is represented by the following equation:

, After cooling and decomposition of the zinc compound by the ice-cold dilute mineral acid, such The w-alkoxymethyl ketonc is reacted with an dried. The ester is then hydrolyzed by refluxing it with a solution of a base, such as sodium hydroxide. The corresponding salt of the p-R-phydroxy-p-alkoxymethyl propionic acid thus formed is converted to the free acid by acidificationwith a suitable mineral acid, such as su1-- furic acid. The action which takes place is represented by the following equation:

(s on 011 R. .-0H, HOH R.J.--CH1 RaOH H, 00R, H, 00H

For substantially complete isolation of the ,8-R-,B-hydroxy-,B-alkoxymethy1 propionic acid, the fi-R-p-hydroxy-pealkoxymethyl propionic acid is preferably extracted with ether from the reaction mixture. The ether may then be removed by distillation to yield the desired product.

The fl-R-p-hydroxy-p-alkoxymethyl propionic acid or the ester of the acid is heated, preferably between C. and C. for a period of about one hour in the presence of an acid dehydrating ent selected from the class which consists of acid sulfates of the alkali metals, such as potassium acid sulfate or sodium acid sulfate, anhydrous oxalic acid and the monoalkaline salts of phosphoric acid, such as monosodium phosphate.

The action which. takes place may be represented by the following equation: (7) H dehydrating agent R. .-CH1 v R.C..=CH R 05 H O 21H: OOH g1 =C 0 Typical examples of the compositions of this invention and the methods of preparing them are as follows:

ExAmrLs l.--Preparction o p-phenyl-N- 'ybutyrolactone furic acid. The benzene layer, which contains the ethyl p-phenyl-s-hydroxy-fl-methoxymethyl propionate is separated and dried with anhydrous sodium sulfate. The benzene solution is then evaporated and the resulting oil is distilled. The ethyl e-phenyl-p-hydroxy=p-methcxymethyl propionate boils at about 112 C., corrected, at 2 mm.

The reaction which takes place may be represented by the following equation:

) Grimes BICHCOOCIB-l t in.

l I OH -ig assarss This ester is saponifled by boiling with a 5 percent solution of sodium hydroxide in percent alcohol for about one hour. The solution is then cooled to room temperature and acidified with a mineral acid, such as hydrochloric acid. The

free acid, which is p-iphenyl-p-hydroxy-p-methoxymethyl propionic acid, is extracted with ether and slowly crystallizes after removal of the solvent. Preferably, it is recrystallized from petroleum ether. It melts at about C., corrected.

10 g. of this acid are heated in a Claisen flask reduced pressure. The lactone' distills as a rapidly cryst'allizing oil which boils at (7., corrected, at 2 mm. pressure.

lization from water, the material melts at about 94 0., corrected. It gives no depression in melting point when mixed with a lactone prepared in accordance with the method disclosed in the copending application of Elderfleld and Rubin Serial No. 384,586, filed March 21, 1941. The p-phenyl-M'w-butyrolactone may be represented by the following formula:

A solution of 35 g. of ethyl bromoacetate in 25 cc. of dry benzene is added drop-wise to a boil ing mixture of 38 g. oi p-methoxyphenyl-omethoxymethyl iretone, 20.9 g. of granulated zinc and 175 cc. of dry benzene in a flask equipped with a reflux condenser and stirrer. Prefer-r ably, the solution of ethyl bromoacetate is added during the course of about an hour with constant stirring, and the mixture is then refluxed for 3 hours longer. The reaction mixture which contains the desired zinc complex is treated with dilute hydrochloric acid and the benzene layer is separated and dried with sodium sulfate. Durins; this time the desired ethyl p-(p-methoxyphenyl) -p-methoxymethyl propionate is formed. After removal of the benzene, the product is dis!- tilled at reduced pressure. It boils at about 152 C. to C., corrected, at 0.6 mm. pressure. An analysis reveals 62.9 percent carbon and 7.8 percent hydrogen which compares with theoretical values or 62.7 percent carbon and 7.5 percent hydrogen. The desired product may be represented by the following formula:

v I, on

* C lOi-EHr Ha, O0CrH| The ethyl p-(p-mthoxyphenyl)-s-hydroxy pmethoxymethyl propionate is treated with an alkaline solution exactly as in Examplel. During this time (p-methoxyphenyl) -p-hydroxyp-methoxymethyl propionic acid is formed. An

analysis reveals the presence of 60.0 percent carbon and 6.9 percent hydrogen which compares with theoretical values of 60.0 percent carbon and 6.7 percent hydrogen.

The B (p methoxyphenyl) p hydroxy-pmethonmethyl propionic acid .is heated* with potassium bisulfate in the same manner as the analogous compound is treated in Example 1 to form n (p methoxyphenyl) -A'-"-'y-butyroiactone. This latter compound is refluxed in a mixture 0133 parts of 48 percent aqueous; hydrobromic acid and 2 parts of glacial acetic acid for about 3 hours. The desired p-(p-hydroxyphenyl) -A-'-'y-butyrolactone is formed during this times The reaction mixture is poured into ice water and the desired lactone, which is substantlally insoluble, is filtered off. The lactone I may be recrystallized preferably from dilute alco- This is the desired fi-phenyl-A-'-'y-butyrolactone. After recrystalhol or from water, and melts at about 245 C.,

corrected. This lactone is represented by the following formula: V (11) Y a l =0 The lactone prepared by this method gives no 1 depression in melting point when mixed with I the EXAIPL: 3

Preparation of p- (p-naphthvl) -A'-'- hutyrolactonc p-Naphthyl methoxymethyl ketone is prepared in the same manner as the analogous compound described in Example 1, and the ketone is reacted with ethyl bromoacetate in the presence of zinc as described for-the analogous compound in Example 1 to produce ethyl p-(p-naphthyD-p-hydroxy-p-methoxymethyl propionate. This ester is heated with potassium bisulfate exactly as described in Example 1 to produce 3- (p-naphthyl) A--' -lactone. The p-(fl-naphthyl) -A-'--y-butyrolactone is extracted with ether and the ether containing th lactone is driedlwith anhydrous sodium sulfate. The ether solution is evaporated to dryness and the residue, which consists of the desired lactone, is recrystallized from alcohol.

This la ctone is represented by the following for mula:

RC=CH 0 in which R is an aryl group.

' 2. ,6-Phenyl-A-"-' -butyrolactone which is represented by the following formua:

3. p-(s-Naphthyl)-A"--' -butyrolactone which is presented by the following formula:

c,=cn l i (5th (|}=O WV 0 4. The process of preparing a p-substituted- A--'y-butyrolactone which comprises subjecting a compound represented by the following formula:

RMg--X' in which R is an aromatic group, and X is a halogen of the class which consists of chlorine, bromine, and iodine to the action of an alkoxyaceton'itrile, treating the resulting product with an aqueous solution to form-an n-alkoxymethyl- R-ketone, reacting the said u-alkoxymethyl-R- ketone with an ester of a haloacetic acid selected from the class which consists of chloroacetic acid, bromoacetic acid, and iodoacetic acid in the presence of zinc, treating the resulting product with an aqueous acid solution to form an ester of p-R-B-hydroxy-fl-alkoxymethyl propionic acid, subjecting the said ester of p-R-p-hydroxy-p-alkoxymethyl propionic acid to the action of a base in a suitable solvent to form p-R-p-hydroxy-palkoxymethyl propionic acid and treating said p-R-p-hydroxy-p-alkoxymethyl propionic acid with a substance selected from the class which consists of acid sulfates of alkali metals, anhydrous oxalic acid, and monoalkaline salts of phos phoric acid. 7

5. The process of preparing a p-substituted- A'-'-q-butyrolactone which comprises subjecting acompound represented by the following formula:

in which R is an aromatic group, and X is a halogen of the class which consists of chlorine, bromine, and iodine to the action of an alkoxyacetonitrile, treating the resulting product with a dilute acid to form an w-alkoxymethyl-R- ketone, reacting the said u-alkoxymethyl-R- and 180 C.

6. The process of preparing a ,B-substituted- A-'-'y-butyrolactone which comprises treating a member of the class which consists of p-R-p-hydroxy-fl-alkoxymethyl propionic acids and derivatives of p-R-p-hydroxy-p-alkoxymethyl propionic acids; in which R represents an aromatic group, in the presence of a substance selected from the class which consists of acid sulfates'of alkali metals, anhydrous oxalic acid and monoalkaline salts of phosphoric acid.

'7. p-(p Hydroxyphenyl) -A"-'y butyrolactone which is represented by the following formula:

ROBERT c. mbnnrmn. mm RUBIN. 

